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1.
J Natl Compr Canc Netw ; 21(5): 503-513, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37156478

RESUMEN

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.


Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Neoplasias Cutáneas , Adulto , Humanos , Células Dendríticas/patología , Neoplasias Hematológicas/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Oncología Médica , Neoplasias Cutáneas/diagnóstico
2.
Phys Rev Lett ; 129(22): 221602, 2022 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-36493434

RESUMEN

We derive a nonperturbative, Lagrangian-level formulation of the double copy in two spacetime dimensions. Our results elucidate the field theoretic underpinnings of the double copy in a broad class of scalar theories which can include masses and higher-dimension operators. An immediate corollary is the amplitudes-level double copy at all orders in perturbation theory. Applied to certain integrable models, the double copy defines an isomorphism between Lax connections, Wilson lines, and infinite towers of conserved currents. We also implement the double copy at the level of nonperturbative classical solutions, both analytically and numerically, and present a generalization of the double copy map that includes a fixed tower of higher-dimension corrections given by the Moyal algebra.

3.
J Natl Compr Canc Netw ; 20(2): 106-117, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35130502

RESUMEN

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.


Asunto(s)
Síndromes Mielodisplásicos , Predisposición Genética a la Enfermedad , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Guías de Práctica Clínica como Asunto , Pronóstico
4.
Am J Hematol ; 95(7): 792-798, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32242967

RESUMEN

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.


Asunto(s)
Antineoplásicos/efectos adversos , Fusariosis , Fusarium , Infecciones Fúngicas Invasoras , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Scedosporium , Anciano , Antineoplásicos/administración & dosificación , Femenino , Fusariosis/inducido químicamente , Fusariosis/epidemiología , Fusariosis/prevención & control , Humanos , Incidencia , Infecciones Fúngicas Invasoras/inducido químicamente , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/prevención & control , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/epidemiología , Estudios Retrospectivos , Factores de Riesgo
5.
Clin Infect Dis ; 68(12): 2003-2009, 2019 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-30256954

RESUMEN

BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients. METHODS: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse. RESULTS: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed. CONCLUSIONS: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.


Asunto(s)
Profilaxis Antibiótica , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/etiología , Infecciones por Clostridium/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hipersensibilidad/complicaciones , Receptores de Trasplantes , Vancomicina/administración & dosificación , Administración Oral , Adulto , Anciano , Profilaxis Antibiótica/métodos , Clostridioides difficile/inmunología , Infecciones por Clostridium/mortalidad , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Hipersensibilidad/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tiempo de Tratamiento , Trasplante Homólogo/efectos adversos , Adulto Joven
6.
Biol Blood Marrow Transplant ; 25(3): 515-521, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30315941

RESUMEN

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.


Asunto(s)
Antagonistas de los Receptores CCR5/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Maraviroc/uso terapéutico , Receptores CCR5/deficiencia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/mortalidad , Trasplante de Células Madre Hematopoyéticas/normas , Humanos , Masculino , Maraviroc/farmacología , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento , Donante no Emparentado
7.
J Oncol Pharm Pract ; 25(8): 2035-2037, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30537918

RESUMEN

We describe a case of dose-related periorbital edema in a patient with FLT3-mutated acute myeloid leukemia taking sorafenib and voriconazole that resolved following sorafenib dose reduction. We hypothesize that the mechanism of this adverse event may be related to the inhibition of platelet-derived growth factor receptor (PDGFR) by sorafenib. Clinicians should be aware of this possible dose-related adverse event and the potential role of sorafenib dose reduction when on concurrent voriconazole.


Asunto(s)
Edema/inducido químicamente , Leucemia Mieloide Aguda/tratamiento farmacológico , Sorafenib/administración & dosificación , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Humanos , Masculino , Mutación , Sorafenib/efectos adversos , Voriconazol/administración & dosificación , Tirosina Quinasa 3 Similar a fms/genética
8.
Invest New Drugs ; 36(4): 657-666, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29607465

RESUMEN

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.


Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Sirolimus/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Mitoxantrona/uso terapéutico , Fosforilación/efectos de los fármacos , Proyectos Piloto , Inducción de Remisión/métodos , Transducción de Señal/efectos de los fármacos
10.
Cancer ; 123(3): 449-458, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-27690182

RESUMEN

BACKGROUND: This analysis of the myeloproliferative neoplasm (MPN) Landmark survey evaluated gaps between patient perceptions of their disease management and physician self-reported practices. METHODS: The survey included 813 patient respondents who had MPNs (myelofibrosis [MF], polycythemia vera [PV], or essential thrombocythemia [ET]) and 457 hematologist/oncologist respondents who treated patients with these conditions. RESULTS: Greater proportions of physician respondents reported using prognostic risk classifications (MF, 83%; PV, 59%; ET, 77%) compared with patient recollections (MF, 54%; PV, 17%; ET, 31%). Most physician respondents reported that their typical symptom assessments included asking patients about the most important symptoms or a full list of symptoms, whereas many patient respondents reported less specific assessments (eg, they were asked how they were feeling). Many patient respondents did not recognize common symptoms as MPN-related. For example, approximately one-half or more did not believe difficulty sleeping resulted from their MPN (MF, 49%; PV, 64%; ET, 76%). Physician respondents underestimated the proportion of patients who had symptomatic PV or ET at diagnosis compared with patient respondents. There was discordance regarding treatment goals: among patient respondents with MF or PV, "slow/delay progression of condition" was the most important treatment goal, whereas physician respondents reported "symptom improvement" and "prevention of vascular/thrombotic events," respectively. Finally, more than one-third of patient respondents were not "very satisfied" with their physician's overall management/communication. CONCLUSIONS: The care and satisfaction of patients with MPN may be improved with increased patient education and improved patient-physician communication. Cancer 2017;123:449-458. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.


Asunto(s)
Policitemia Vera/epidemiología , Mielofibrosis Primaria/epidemiología , Trombocitemia Esencial/epidemiología , Trombosis/epidemiología , Femenino , Humanos , Masculino , Oncólogos , Educación del Paciente como Asunto , Pacientes , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/patología , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/patología , Pronóstico , Factores de Riesgo , Encuestas y Cuestionarios , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/patología , Trombosis/tratamiento farmacológico , Trombosis/patología , Estados Unidos
11.
Ann Emerg Med ; 69(2): 218-226, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27974170

RESUMEN

Significant evidence identifies point-of-care ultrasound (PoCUS) as an important diagnostic and therapeutic tool in resource-limited settings. Despite this evidence, local health care providers on the African continent continue to have limited access to and use of ultrasound, even in potentially high-impact fields such as obstetrics and trauma. Dedicated postgraduate emergency medicine residency training programs now exist in 8 countries, yet no current consensus exists in regard to core PoCUS competencies. The current practice of transferring resource-rich PoCUS curricula and delivery methods to resource-limited health systems fails to acknowledge the unique challenges, needs, and disease burdens of recipient systems. As emergency medicine leaders from 8 African countries, we introduce a practical algorithmic approach, based on the local epidemiology and resource constraints, to curriculum development and implementation. We describe an organizational structure composed of nexus learning centers for PoCUS learners and champions on the continent to keep credentialing rigorous and standardized. Finally, we put forth 5 key strategic considerations: to link training programs to hospital systems, to prioritize longitudinal learning models, to share resources to promote health equity, to maximize access, and to develop a regional consensus on training standards and credentialing.


Asunto(s)
Internado y Residencia/métodos , Sistemas de Atención de Punto , Ultrasonografía , África , Algoritmos , Competencia Clínica , Curriculum , Países en Desarrollo , Medicina de Emergencia/educación , Medicina de Emergencia/organización & administración , Humanos , Internado y Residencia/normas
12.
BMC Cancer ; 16: 167, 2016 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-26922064

RESUMEN

BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. METHODS: The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. RESULTS: The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). CONCLUSIONS: These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.


Asunto(s)
Trastornos Mieloproliferativos/epidemiología , Calidad de Vida , Actividades Cotidianas , Adulto , Anciano , Anciano de 80 o más Años , Manejo de la Enfermedad , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/mortalidad , Trastornos Mieloproliferativos/terapia , Evaluación del Resultado de la Atención al Paciente , Factores de Riesgo , Estados Unidos/epidemiología
13.
Am J Hematol ; 91(9): 883-7, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27197602

RESUMEN

Reduced intensity allogeneic stem cell transplantation (RI alloSCT) is a potentially curative treatment approach for patients with myelodysplastic syndrome (MDS). It is currently unclear if older related donors are better than younger unrelated donors for patients with MDS undergoing RI alloSCT. We retrospectively studied 53 consecutive MDS patients who underwent RI alloSCT between April 2007 and June 2014 and evaluated associations between donor type and outcomes with adjustment for significant covariates. 34 patients (median age: 64 years) and 19 patients (median age: 60 years) received allografts from unrelated and related donors, respectively. Unrelated donors were younger than related donors (median age: 32 vs. 60 years, P < 0.0001). There were no significant differences in baseline disease characteristics of patients receiving allografts from related or unrelated donors. Patients who received allografts from unrelated donors had a lower relapse risk (adjusted hazard ratio [aHR] = 0.35, P = 0.012) and improved relapse-free survival (aHR = 0.47, P = 0.018). HLA mismatched unrelated donors were associated with a higher risk of grade 2-4 acute graft versus host disease (GVHD) (HR = 4.64, P = 0.002) without an accompanying increase in the risk of non-relapse mortality (P = 0.56). Unrelated donors provided a higher mean CD8 cell dose (P = 0.014) and were associated with higher median donor T cell chimerism at day 60 (P = 0.003) and day 100 (P = 0.03). In conclusion, patients with MDS who received allografts from unrelated donors had a lower risk of relapse and improved relapse-free survival when compared to patients who received allografts from related donors. These findings should be confirmed in a prospective study. Am. J. Hematol. 91:883-887, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Donantes de Sangre , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Recurrencia , Estudios Retrospectivos , Trasplante Homólogo , Donante no Emparentado , Adulto Joven
14.
Am J Hematol ; 91(5): 453-60, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26858124

RESUMEN

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Transfusión de Linfocitos , Subgrupos de Linfocitos T/trasplante , Adulto , Anemia Refractaria con Exceso de Blastos/terapia , Factor Activador de Células B/biosíntesis , Conservación de la Sangre , Antígenos CD28/inmunología , Complejo CD3/inmunología , Células Cultivadas/trasplante , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/mortalidad , Criopreservación , Citocinas/análisis , Relación Dosis-Respuesta Inmunológica , Estudios de Factibilidad , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/etiología , Histocompatibilidad , Humanos , Recién Nacido , Leucemia Mieloide Aguda/terapia , Transfusión de Linfocitos/efectos adversos , Masculino , Dosis Máxima Tolerada , Proteínas de la Membrana/biosíntesis , Persona de Mediana Edad , Neutrófilos/trasplante , Especificidad del Receptor de Antígeno de Linfocitos T , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento
15.
Curr Opin Hematol ; 22(2): 97-107, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25575037

RESUMEN

PURPOSE OF REVIEW: Despite successful remission induction in 60-80% of patients with newly diagnosed acute myeloid leukemia, there remain a significant number of patients who exhibit primary refractory disease. Here we examine the data for predicting likelihood of having refractory disease, available therapeutic options, and how to decide the appropriate treatment option for a patient. RECENT FINDINGS: Recently identified recurrent molecular mutations and early response to chemotherapy as determined by kinetics of peripheral blast clearance or nadir bone marrow biopsy assist in determining the likelihood of primary refractory disease. Newer cytotoxic agents, used as salvage chemotherapy, or in novel conditioning regimens for hematopoietic stem cell transplant may represent improvement over prior regimens. FMS-like tyrosine kinase 3 gene inhibitors and other targeted therapies currently in clinical trials show promise for select patients. Hypomethylating agents provide benefit to patients who are not candidates for other therapies. SUMMARY: Recent advances in understanding the pathogenesis of acute myeloid leukemia have not yet translated to a significantly improved outlook for patients with refractory disease. While there are several therapeutic options, outcomes remain poor and further studies are needed to identify and validate novel approaches.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Pronóstico , Inducción de Remisión , Terapia Recuperativa , Resultado del Tratamiento
16.
Biol Blood Marrow Transplant ; 21(4): 768-71, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25543093

RESUMEN

The incidence and risk factors for acute cholecystitis after allogeneic hematopoietic stem cell transplantation (HSCT) are not well defined. Of 644 consecutive adult transplants performed at our institution between 2001 and 2011, acute cholecystitis occurred in the first year of transplant in 32 patients (5.0%). We conducted 2 retrospective case-control studies of this population to determine risk factors for cholecystitis after HSCT and to evaluate the performance of different methods of imaging to diagnosis cholecystitis in patients undergoing HSCT compared with non-HSCT patients. In the HSCT population, development of cholecystitis was associated with an increased 1-year overall mortality rate (62.5% versus 19.8%, P < .001). The risk of developing cholecystitis was higher in patients who received total parenteral nutrition (TPN) (adjusted odds ratio, 3.41; P = .009). There was a trend toward more equivocal abdominal ultrasound findings in HSCT recipients with acute cholecystitis compared with nontransplant patients (50.0% versus 30.6%, P = .06). However, hepatobiliary iminodiacetic acid (HIDA) scans were definitively positive for acute cholecystitis in most patients in both populations (80.0% of HSCT recipients versus 77.4% of control subjects, P = .82). In conclusion, acute cholecystitis is a common early complication of HSCT, the risk is increased in patients who receive TPN, and it is associated with high 1-year mortality. In HSCT recipients with findings suggestive of acute cholecystitis, especially those receiving TPN, early use of HIDA scan may be considered over ultrasound.


Asunto(s)
Colecistitis/diagnóstico , Colecistitis/epidemiología , Colecistitis/etiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Nutrición Parenteral/efectos adversos , Enfermedad Aguda , Adulto , Anciano , Aloinjertos , Femenino , Neoplasias Hematológicas/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
17.
Biol Blood Marrow Transplant ; 20(11): 1758-66, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25016197

RESUMEN

The success of hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Donantes de Tejidos , Quimera por Trasplante , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven
18.
Leuk Res Rep ; 21: 100408, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38269085

RESUMEN

Near early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare hematologic malignancy, for which second line therapeutic options are limited. T-cell leukemias are also rarely associated with leukemia cutis, which is more often seen in leukemias of myeloid origin. We present the case of an adult male diagnosed with near ETP-ALL, with IDH2 and DNMT3A mutations, suggestive of a myeloid origin, and leukemia cutis. After the patient progressed on hyper-CVAD and nelarabine, we treated him with the BCL-2 inhibitor venetoclax and the hypomethylating agent decitabine. The regimen induced a rapid bone marrow response and resolution of the leukemia cutis.

19.
Leuk Lymphoma ; 65(4): 503-510, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38259250

RESUMEN

Pelabresib (CPI-0610), a BET protein inhibitor, is in clinical development for hematologic malignancies, given its ability to target NF-κB gene expression. The MANIFEST phase 1 study assessed pelabresib in patients with acute leukemia, high-risk myelodysplastic (MDS) syndrome, or MDS/myeloproliferative neoplasms (MDS/MPNs) (NCT02158858). Forty-four patients received pelabresib orally once daily (QD) at various doses (24-400 mg capsule or 225-275 mg tablet) on cycles of 14 d on and 7 d off. The most frequent drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) was 225 mg tablet QD. One patient with chronic myelomonocytic leukemia (CMML) showed partial remission. In total, 25.8% of acute myeloid leukemia (AML) patients and 38.5% of high-risk MDS patients had stable disease. One AML patient and one CMML patient showed peripheral hematologic response. The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125 mg tablet QD.CLINICAL TRIAL REGISTRATION: NCT02158858.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Antineoplásicos/uso terapéutico , Comprimidos/uso terapéutico
20.
Transplant Cell Ther ; 29(2): 113-118, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36336258

RESUMEN

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Busulfano/uso terapéutico , Clofarabina , Estudios Retrospectivos , Agonistas Mieloablativos , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trastornos Mieloproliferativos/terapia , Trastornos Mieloproliferativos/complicaciones , Leucemia Mieloide Aguda/terapia , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Recurrencia
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